Objective To compare the simple cases of hand-foot-mouth disease(HFMD) with HFMD patients complicated with encephalitis and HFMD cases complicated with pulmonary edema (PE). To explore predictor factors of disease progression and unfavorable prognosis. Methods Forty-one EV71-infected children admitted to the Fuyang First People's Hospital in Anhui Province from March to May in 2008 were investigated in the research, who were classified as encephalitis-complicated cases ( encephalitis group, n = 15 ), PE-complicated cases ( PE group, n = 15 ) and simple cases (simple group, n= 11 ). Their clinical manifestation, laboratory findings, and immunophenotypes of peripheral blood lymphocyte were analyzed to find predictors associated with disease progression and unfavorable outcomes. Results The mortality rate in PE group was 66.7%, which was significantly higher than that in encephalitis group. Ninty-three point three percent cases in PE group and encephalitis group were younger than 3 years old, with statistic difference compared to simple group. Patients in PE group had higher total blood white cell (WBC) counts and higher absolute neutrophil counts and tended to have higher breathing rate, heart i'ate and glucose level than encephalitis group. The percentages of T cells and natural killer (NK) cells were significantly lower among patients complicated with encephalitis than simple HFMD patients.Conclusions PE is one predictor for poor prognosis. Factors correlated with unfavorable outcome include high WBC, high absolute neutrophil counts; elevated breathing rate, heart rate and glucose level. The immunophenotypes of peripheral blood lymphocytes can also predict the disease progression.